THE RELATION OF DOSAGE TO THE DEVELOPMENT OF TOLERANCE TO MORPHINE IN DOGS

1. Normal dogs, upon recovery from the convulsant effects of a large dose of morphine, usually show persistence of the gastrointestinal but not of the narcotic effects of the drug. They are highly resistant to the narcotic effects of otherwise depressant doses and upon daily repetition of such doses they uniformly survive and become as tolerant within a week as they ever become, even after many months of daily injections. This is regarded as evidence that cerebral cells, like the blood vessels and vasomotor and respiratory centers, rapidly become resistant to the depressant effects of morphine when exposed to high concentrations of the drug. 2. Control animals given daily doses of 30 to 60 mgm. per kilogram showed a high mortality, but the survivors became tolerant within a month. On 2 and 10 mgm. per kilogram tolerance appeared much more slowly, fifteen to twenty weeks being required to make it maximal. 3. Dogs that had finally become tolerant to 2 or 10 mgm. per kilogram daily showed no appreciable narcosis when given 100 mgm. per kilogram, though marked gastro-intestinal effects were elicited. Tolerance to the narcotic effects need not, therefore, be developed in staircase fashion. 4. There is reason to believe that man also becomes tolerant much less readily to small doses of morphine than to larger or increasing ones, but that once tolerance has appeared much larger doses produce little or no narcosis. 5. By way of explanation, it is suggested that tolerance is the result of a change which occurs in depressible cells as soon as the concentration of morphine in contact with them has reached a certain critical level, and that the change is reversed as soon as the concentration falls below this level. This cell tolerance reaction appears to occur most readily and completely in blood-vessels and in respiratory and vasomotor centers, less so in the cerebrum, and least in the gastro-intestinal tract, but it also is reversed less rapidly in the cerebrum than in the circulation. 6. This conception, when applied to the phenomena of human tolerance, finds a certain amount of supporting evidence and no insuperable objections. 7. It is suggested that abstinence symptoms in dog and man, in so far as they have an organic cause, may be the external manifestations of the reversal of the cell tolerance reaction when morphine is withheld.